Association of amino acid substitution polymorphisms in DNA repair genes TP53, POLI, REV1 and LIG4 with lung cancer risk

Tokuki Sakiyama, Takashi Kohno, Sachiyo Mimaki, Tsutomu Ohta, Noriko Yanagitani, Tomotaka Sobue, Hideo Kunitoh, Ryusei Saito, Kimiko Shimizu, Chie Hirama, Junko Kimura, Go Maeno, Hiroshi Hirose, Takashi Eguchi, Daizo Saito, Misao Ohki, Jun Yokota

doi:10.1002/ijc.20790

<jats:title>Abstract</jats:title><jats:p>Single nucleotide polymorphisms (SNPs) were searched for in 36 genes involved in diverse DNA repair pathways, and 50 nonsynonymous (associated with amino acid changes) SNPs identified were assessed for associations with lung cancer risk by a case‐control study consisting of 752 adenocarcinoma cases, 250 squamous cell carcinoma cases and 685 controls. An SNP, Arg72Pro, of the <jats:italic>TP53</jats:italic> gene encoding a DNA damage response protein showed the strongest association with squamous cell carcinoma risk (OR Pro/Pro <jats:italic>vs</jats:italic>. Arg/Arg = 2.2), while 2 other SNPs, Phe257Ser of the <jats:italic>REV</jats:italic> gene encoding a translesion DNA polymerase and Ile658Val of the <jats:italic>LIG4</jats:italic> gene encoding a DNA double‐strand break repair protein, also showed associations (OR Ser/Ser <jats:italic>vs</jats:italic>. Phe/Phe = 2.0 and OR Ile/Val <jats:italic>vs</jats:italic>. Ile/Ile = 0.4, respectively). An SNP, Thr706Ala, in the <jats:italic>POLI</jats:italic> gene encoding another translesion DNA polymerase was associated with adenocarcinoma and squamous cell carcinoma risk, particularly in individuals of ages < 61 years (OR Ala/Ala + Ala/Thr <jats:italic>vs</jats:italic>. Thr/Thr = 1.5 and 2.4, respectively). <jats:italic>POLI</jats:italic> is the human counterpart of <jats:italic>PolI</jats:italic>, a strong candidate for the <jats:italic>Par2</jats:italic> (<jats:italic>pulmonary adenoma resistance 2</jats:italic>) gene responsible for adenoma/adenocarcinoma susceptibility in mice. The present results suggest that these 4 SNPs function as genetic factors underlying lung cancer susceptibility by modulating activities to maintain the genome integrity of each individual. © 2004 Wiley‐Liss, Inc.</jats:p>

Association of amino acid substitution polymorphisms in DNA repair genes <i>TP53</i>, <i>POLI</i>, <i>REV1</i> and <i>LIG4</i> with lung cancer risk

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